17{60 ,21-orthobutyrates of 6{60 , 9{60 -difluoro-hydrocortisone and 6{60 , 9{60 -difluoroprednisolone, compositions containing same and the use thereof as anti-inflammatory agents

ABSTRACT

There have been prepared the new 17 Alpha , 21-orthobutyrates of 6 Alpha , 9 Alpha -difluorohydrocortisone and 6 Alpha , 9 Alpha difluoroprednisolone -difluoroprednisolone useful as antiinflammatory agents. The compounds may be used in the form of pharmaceutical formulations in corticoid anti-inflammatory therapy.

United States Patent [191 Ercoli et al.

[ Jan. 29, 1974 I M r-2?, 1962 112911! e de 17a,21-ORTI-IOBUTYRATES OF601, 9a-DIFLUORO-HYDROCORTISONE AND 611, 9a-DIFLUOROPREDNISOLONE,COMPOSITIONS CONTAINING SAME AND THE USE THEREOF AS ANTI-INFLAMMATORYAGENTS lnventors: Alberto Ercoli, Milan; Rinaldo Gardi, Carate Brianza,both of Italy Assignee: Warner-Larnbert Company, Morris Plains, NJ.

Filed: Nov. 26, 1971 Appl. No.: 202,686

Related US. Application Data Division of Ser. No. 55,260 July 15, 1970,which was a continuation-in-part of Ser. No. 716,287,

US. Cl. 424/241 Int. Cl A61k 17/00 Field of Search 424/241 ReferencesCited UNITED STATES PATENTS 6/1958 Spero et al.... 260/239.55

3,147,249 9/1964 Ercoli et al, 260/239.55 3,152,154 10/1964 Ercoli etal. 260/397.45 3,297,729 l/l967 Mancini et a] 260/397.4

3,312,590 4/1967 Elks et al. 424/243 3,312,591 4/1967 Elks et al 424/2433,376,193 4/1968 Elks et al. 424/243 3,383,394 5/1968 Weber et al.260/397.45

Primary Examiner-Shep K. Rose Attorney, Agent, or Firm-Albert H. Graddiset a1.

7 No Drawings 17a,2l-ORTHOBUTYRATES OF 611, Qc -DIFLUQRO-HYDROCORTISONEAND 6a, 9a-DIFLUOROPREDNISOLONE, COMPOSITIONS CONTAINING SAME AND THEUSE THEREOF AS AN NELAMMAIQKX AQENIS v.

This application is a division of application Ser. No.

55,260, filed July 15,1960, which application was a continuation-in-partof application Serial No. 716,287, filed Mar. 27, 1968, bothapplications now abandoned.

OCHa

wherein the dotted line indicates the possible presence of a double bondat the l(2)-position.

These compounds show anti-inflammatory properties particularly high incomparison with those of the known 60:, Qa-difluorohydrocortisone and6a, 9a-difluoroprednisolone and of their 2l-esters. They possessincreased topical and systemic activity and in addition show theadvantage of a sustained and prolonged anti-inflammatory effect onparenteral administration, as evidenced by tests on animals over a 7days period after a single injected therapeutic dose. The new 17, 2 l-orthobutyrates of this invention are highly effective and permit toobtain an anti-inflammatory response of longer duration than that given10 times the therapeutic dose of 6a, 9a-difluorohydrocortisone. Thisprolongation of activity found in a 17, 21- orthoester structure isunexpected since it is known that the 17, 2 I-steroid orthoesters areactive only when topically applied but of low activity when administeredsystemically.

On account of their particular properties, the new 17, 2l-orthobutyratesof this invention are useful in the form of pharmaceutical compositionsfor the topical and systemic treatment of inflammatory conditions anddiseases.

The high potency and the prolonged action of the compounds of thisinvention permit a significant reduction of dosage in steroid therapy.In fact, the 17, 21- orthobutyrates can be administered in extremely lowdosage thereby minimizing the side effects which can result from aprolonged administration of antiinflammatory steroids.

The compounds of this invention are utilized in the form ofpharmaceutical compositions in combination with a pharmaceuticallyacceptable carrier or diluent suitable for oral, parenteral or topicalapplication. In the form of injectable preparations the 17,21-orthobutyrates of 6a, 9a-difluorohydrocortisone and 6a,9a-difluoroprednisolone exhibit their prolonged antiinflammatory actionand these perparations are obtained in the form of sterile aqueoussuspensions or oily solutions for intramuscular, subcutaneous andintravenous use. When orally administered the active ingredients arecompounded with the usual carriers suitable for oral ingestion in theform of pills, tablets, capsules and syrups. V

For topical application the active ingredients are incorporated in theusual compatible vehicles utilized for the preparation of powders,ointments, lotions, creams, emulsions, drops, sprays and other formsparticularly suitable for dermatological use. The carriers employed arethose which have already been proposed for use in manufacturingpreparations for topical use, such as for example fats of animal originand vegetable oils, saturated or unsaturatedvfatty acids, aluminiumstearate, alcohols, poly-alcohols, such as for example glycerol,propylene or polyethylene glycols, waxes, aliphatic hydrocarbons orlanolin, together with comparatively high quantities of water. Othercarriers which can be used are hydrophilic bases, cholesterol, vaseline,vaseline oil, silicones which are physiologically inert, sodium alginateand in addition stabilizing, thickening and colouring agents andperfumes.

The compositions of the present invention can also contain preservativeor bacteriostatic agents such as for example esters of p-hydroxy benzoicacid, i.e., methyl-, ethylor propyl-p-hydroxy benzoate, mercuricderivatives such as for example the merthiolate, or quaternary ammoniumderivatives such as for example cetyltrimethyl-ammonium bromide, whichbesides the surface active action possess a good bacteriostaticactivity.

Other active ingredients capatible with the new steroids of thisinvention, such as for example antibiotics, local anesthetics orsulphonamides can also be incorporated in theanti-inflammatorypreparations if these added properties orcharacteristics are desired.

The 17,2l-orthobutyrates of 6a,9a-difluorohydrocortisone and6a,9a-difluoroprednisolone are included in the compositions of thisinvention in an amount sufficient to produce the desired therapeuticefiect upon the inflammatory process or condition. Advantageously thecompositions will contain the active ingredient in an amount of from0.0005% to 5% by weight, and preferably contain the specific activeingredient in an amount of from 0.005% to 05%by. ei t 2 a t Td ir nprove the stability of the active ingredients in the aqueous vehicles it isadvisable to adjust the pH of the compositions to a value not lower than7, for example by adding an organic or inorganic base, such as, forexample, triethan'olamine.

The new 17, 2 l-orthoesters of the present invention are prepared bytreatment of the corresponding diols with methyl-orthobutyrate in thepresence of an acid catalyst. The orthoesterification is'preferablycarried out in elevated temperature (around l00-l 10 C) and theresulting l7a,2l-orthobutyrate of 6a,9a-difluorohydrocortisone or6a,9a-difluoroprednisolone is obtained as a mixture of two epimericorthoesters,

which can be separated according to the usual procedures. in practice weprefer to use the mixture of the two epimers as such for the preparationof the pharmaceutical compositions as described in the experimentalpart.

This invention is illustrated but not limited by the'following examples.

EXAMPLE 1 A mixture of l g of 6a, 9tadifliirdhydrooifisbhj' cc ofmethylorthobutyrate and 10 mg of paratoluenesulfonic acid in 5 cc ofdimethylformamide is maintained overnight under nitrogen stream at 105 C(bath temperature). Then there are added a few drops of pyridine and thesolvent is evaporated under vacuum. The residue is taken up with littlemethanol, filtered and the product crystallized from amethanol-methylene chloride mixture. The 17a, 2 l l '-methoxy)n-butylidenedioxy-6a, Y 9a-difluoro-A -pregnen-l lB-ol-3,20-dione is soobtained; M.P. l88l92 C, [111 84 (dioxane, c= 0.5%). On thin layerchromatography this product appears consisting of two epimers which canbe separated by fractional crystallization. They show slight differencesin melting point and specific rotation, but possess the same degree ofactivity.

' EYAli/TLE '2 1 rnixtureof 2 g o f 6oi;o difluoroprednisolone, 6 cc ofmethylorthobutyrate and 20 mg of p-toluenesulfonic acid in l cc ofdimethylformamide is maintained overnight under nitrogen stream on anoil-bath at l C. Then the mixture is neutralized by addition of a fewdrops of pyridine and concentrated under vacuum to dryness. The residueis taken up with little methanol, filtered and the product crystallizedfrom a methanolmethylene chloride mixture to give the 1701, 2l-(l'-methoxy)-n-butylidenedioxy-6a, 9a-difluoro-A--pregnadien-l1B-ol-3,20-dione; M.P. l94l98 C; [011 58 (dioxane, c=0.5%). On thinlayer chromatography this product appears consisting of two epimerswhich can be separated by fractional crystallization. They show slightdifferences in melting point and specific rotation, but possess the samedegree of activity.

The test steroid as a microcrystalline suspension in 0.2 7

ml of aqueous carboxymethyl cellulose was subcutaneously injected in asingle dose. Eight days later the animals were sacrificed and theexudate was collected and measured, the volume of exudate beinginversely proportional to the anti-inflammatorypotency of the steroid.

By this procedure the sustained activity of the two 17, 2lorthobutyrates of this invention was determined and compared with thatof the parent steroids and of two structurally related 17.2l-orthoesters well known Single doso/ rat Exudate, Compound (02 ml.suspending vehicle) Moles Mg. ml.

Control 22. Oil. 86 6a,9a-difluoroprednisolone 17,21-methyl- 1 0. 481 3.4:1:0. 56 orthobutyrate 10 4. 81 1. 2=l=0. 746a,9a-d1fluorohydrocortisone 17,21-methyl-{ 1 0. 483 8. 0:1:1. 13orthobutyrate 10 4. 83 0. 9:1:0. 17 6a,9a-difiuoroprednisolone 2i6a,9a-difluorohydrocortisone Betamethasone 17,21-methylorthobu- 1(1)011;;

tyrate Hydrocortisone 17,21-methylorthoval- 1 0. 461 18. 8:1:2. 83 erate10 4. 61 19. 63:2.

EXAMPLE 4 7 An oil solution for parenteral use containing 0.05% byweight of 6a, 9a-difluorohydrocortisone 17a, 2 l -methylorthobutyratewas prepared by dissolving 0.5 g of the active ingredient in one literof sesame oil and transferring the solution to suitable sized sterilevials under aseptic conditions.

In the same manner, 3 g of Wall-methylorthobutyrate of6a,9adifluoroprednisolone were dissolved in 500 cc mixture of sesame oiland olive oil and the limpid solution filled into 0.2 cc soft gelatincapsules for oral use so that each capsule contains 0.3% by weight ofactive ingredient.

EXAMPLE 5 The parenteral aqueous suspension at 0.1% by weight wasprepared with the following ingredients:

611,9a-Difluoroprednisolone 17a,2 1 -methylorthobutyrate- 1 mg Benzylalcohol 0.02ml Polysorbate so U.S.P. -8 mg Water for injection U.S.P. to1 ml.

A similar aqueous suspension at 0.5% by weight had the followingcomposition:

6 b2P01- ljii luoroprediiisolone butyrate 5 mg Polyethylene glycol 400U.S.P. 20 mg Polysorbate 8O U.S.P. 8 mg Water for injection U.S.P. to 1ml l7 oz,2l-methylortho- EXAMPLE 6 Tablets for oral use each containing0.1% by weight of active compound were prepared by mixing theappropriate quantity of 17a, 2l-methylorthobutyrate of 6a,9a-difluorohydrocortisone with lubricants such as magnesium stearate andlactose to form a homogenized mixture which is then compressed intotablets.

Capsules for oral administration were prepared by filling into softgelatin capsules 4 mg of the active ingredient mixed with diluents, suchas powered lactose and powered sucrose.

EXAMPLE 7 An ointment having the following composition was prepared forexternal use following accepted pharmaceutical compounding procedures.

Components Percent (70) By Weight 17a, 21 rnethylorthobutyrate ofdifluoroprednisolone 0.10 Beeswax 5.00 Anhydrous lanolin 5.00 White softparaffin 20.00 Amphocerin K (Dehydag, Deutsche Hydrierwerke G.m.b.H..Dusseldorf) 25.00 Liquid paraffin 14.90

Distilled water adjusted to pH7.5 with triethanolamine 30.00

Melt the beeswax, the lanolin, the white soft paraffin and the liquidparaffin at 70 C, add the active ingredient, then the mixture of theAmphocerin K and the water. Refine twice.

EXAMPLE 8 Hydrophllic ointment having the following composition:

Components Percent By Weight 17a, 21-methylorthobutyrate of 6a,

difl t 2t9nrcd qlo 04300 Propylparahen 0.015 Methylparaben 0.025 Sodiumlaurylsulphate 1.000 Propylene glycol 12.000 Stearyl alcohol 25.000White soft paraffin 25.000 Distilled water adjusted to pH 7.5 withtriethanolamine (to 100%) Melt the stearyl alcohol and the white softparaffin on a steam bath, and warm about 75 C, add a solution of theactive ingredient in the propylene glycol, then the other ingredients,previously dissolved in the water and warmed to 75 C. Stir the mixtureuntil it congeals.

1n the above hydrophilic ointment sodium laurylsulphate can be replacedby polyoxyl 40 stearate in an amount of 5% by weight.

EXAMPLE 9 Cream having the following composition Components Percent (96)By Weight 170:, 2l-methylorthobutyrate of 6a,

9a-dif'luoro-prednisolone 0.050 Cetostearyl alcohol 12.000 White softparaffin 6.480 Liquid paraffin 6.480 lsopropyl stearate 3.240 Propyleneglycol 3.240 Methylparaben 0.180 Propylaparaben 0.050 Tween 80 0.200Polyethylene glycol 6000 4.950

Distilled water adjusted to pH 7.5 with triethanol-amine 63.130

Melt the cetostearyl alcohol, the white soft paraffin, the liquidparaffin and the isopropyl stearate at about C, add a solution of theactive ingredient in the propylene glycol, then the other ingredientspreviously mixed with the water and warmed to 70 C. Refine twice.

Melt the stearyl alcohol, the white soft paraffin and the liquidparaffin at C, add a solution of the active ingredient in the propyleneglycol, then the other ingredients previously mixed withthe water andwarmed to 75 C. Refine twice EXAMPLE 1 l Ointment having the followingcomposition Components Percent By Weight 17a, 2l-methylorthobutyrate of6a,

9a-difluoro-hydrocortisone 0.20 Lanolin 14.45 Liquid paraffin 17.75Neomycin sulphate 0.40 White soft paraffin 67.20

Add the 17a, 21-( l'-methoxy)-n-butylidenedioxy- 6a,9a-difluoro-N-pregnen-l lB-ol3,20-dione and the neomycin sulphate to theother ingredients previously melted at 75 C and refine twice.

In place or besides the neomycin sulphate other topically activeantibiotics can be used, such as colistin sulphate, bacitracin,gramicidin, chloramphenicol or the sulphonamides.

EXAMPLE l2 Ophthalmic ointment having the following compositionComponents Percent I By Weight 1701, 21-methylorthobutyrate of 6a,

9a-difluoroprednisolone 0.025 Liquid paraffin 29.975 White soft paraffin 70.000

Add the active product to the other ingredients, previously sterilizedby heating at 120 C for an hour. Refine twice and distribute intosterile tubes.

EXAMPLE l3 Lotion having the following composition Components Percent(70) By Weight 1701, 21-methylorthobutyrate of 6a,

9a-difluoro hydrocortis0ne 0.4 Ethyl alcohol 400 Water adjusted to pH7.5 with triethanolamine 59.0 Cologne water 0.6

The active product is added to a clear mixture of the other ingredients.

EXAMPLE l4 Lotion having the following composition 1 Components PercentBy Weight. 1701, 2l-methylorthobutyrate of 6a,

Ja-difluoro-prednisolone 0.03 Ethyl alcohol 95 50.00 Propylene glycol20.00 Distilled water adjusted to pH 7.5 with triethanol-amine 29.97

Dissolve the active product in the alcohol and add the solution to aclear mixture of the other ingredients.

EXAMPLE t5 Lotion having the following composition Components Percent ByWeight 170:, ZI-methylorthobutyrate of 6a,

9a-difluoro-hydrocortisone 0.05 Ethyl alcohol 95 40.00 Glycerol 10.00Glycerol 30.00 Distilled water adjusted to pH 7.5 with triethanol-amine19.95

Prepared as described in Example 14. It is to be noted that the term170:, 2 l-methylortho-butyrate of 60:,

9oz-difluorohydrocortisone is the common name used herein for 17a,21-(1'-methoxy)-n-butylidenedioxy- 6a, 9a-difluoro-A -pregnen-l1B-ol-3,-dione. Similarly, the term 170:, 2l-methylorthobutyrate of 6a,9a-difluoroprednisolone is used for 170:, 2l-(1"-methoxy)-n-butylidenedioxy 6a, 9a-difluoro-A" -pregnadien-1 lB-ol-3,20-dione.

We claim: y

l. A compound of formula:

OCHa

wherein the dotted line indicates the possible presence of a double bondat the l(2)-position, in association- CHRT 00153 vvh'i'ifi'ihe dottedline indicates the possible presence of a double bond at thel(2)-position, incorporated in a systemic pharmaceutically acceptablecarrier.

7. A composition as claimed in claim 5 wherein th compound 7 is 1 701,21 l'-methoxy)-n-butylidenedioxy-6a, 9a-difluoro-A -pregnen-l lB-ol-3,20-dione.

8. A composition as claimed in claim 5 wherein the compound is 1702, 2l-(1'-methoxy)-n-butylidenedioxy- 9. A pharmaceutical compositionasclaimed in claim 2 for the local treatment of inflammation, wherein thecompound is used in association with a topical pharmaceutical carrier.

10. A composition as claimed in claim 9 wherein the compound is 17a,21-( l '-methoxy)-n-butylidenedioxy- 6a, 9a-difluoro-A -pregnen-l 1,B-ol-3,20-dion e.

11. A composition as claimed in claim 8 wherein the compound is 17a,2l-( 1 -methoxy)-n-butylidenedioxy- 6a,9a-difluoro-A" -pregnadien-11B-ol-3 ,20-dione.

12. A method as claimed in claim 6 wherein from 0.0005% to 5% by weightof the compound is administered.

13. A method as claimed in claim 6 wherein from 0.005% to 0.5% by weightof the compound is administered.

14. A method as claimed in claim 6 wherein the compound is l7a,2 l l'-methoxy)-n-butylidenedioxy- 6a,9a-difluoro-N-pregnen-1 lB-ol-3,20-dione.

15. A method as claimed in claim 6 wherein the compound is 1 701,2 l-(l-methoxy)-n-butylidenedioxy- 6a,9a-difluoro-A--pregnadien-l lB-ol-3,20-dione.

UNETED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.5,789,121 Dated January 29, 197

Alberto Ercoli et a1.

Inventor(s) It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

In the ABSTRACT, line 5, cancel "difluoroprednisolone" secondoccurrence. Column 1, line 7, "1960" should read 1970 Column 2, line 25,"aluminium" should read aluminum line LI-Q, "capatible" should readoompatible line 6A, "in" should read at Column L, line 21, "below"should read above Columns 7 and- 8 should appear as shown on theattached sheet.

Signed and sealed this 22nd day of October 1974.

(SEAL) Attest:

McCOY M. GIBSON JR, I c. MARSHALL 'DANN Attesting Officer- Commissionerof Patents FORM PO-1050 (10-69) uscoMM-Dc 60376-P69 u.s sovzwumsmPRINYING OFFxCE: 8 930

2. A composition as claimed in claim 1 containing from 0.0005% to 5% byweight of the active ingredient.
 3. A composition as claimed in claim 1containing from 0.005% to 0.5% by weight of the active ingredient.
 4. Apharmaceutical composition for the treatment of inflammation comprising,as the active ingredient, a compound of formula:
 5. A pharmaceuticalcomposition as claimed in claim 5 having a sustained anti-inflammatoryaction on parenteral administration wherein the compound is used inassociation with a systemic, pharmaceutically acceptable carrier.
 6. Amethod of obtaining a sustained anti-inflammatory action which comprisessystemically administering an effective amount of a compound of formula:7. A composition as claimed in claim 5 wherein the compound is 17 Alpha,21-(1''-methoxy)-n-butylidenedioxy-6 Alpha , 9 Alpha -difluoro- Delta4-pregnen-11 Beta -ol-3,20-dione.
 8. A composition as claimed in claim 5wherein the compound is 17 Alpha , 21-(1''-methoxy)-n-butylidenedioxy-6Alpha ,9 Alpha -difluoro- Delta 1,4-pregnadien-11 Beta -ol-3,20-dione.9. A pharmaceutical composition as claimed in claim 2 for the localtreatment of inflammation, wherein the compound is used in associationwith a topical pharmaceutical carrier.
 10. A composition as claimed inclaim 9 wherein the compound is 17 Alpha ,21-(1''-methoxy)-n-butylidenedioxy-6 Alpha , 9 Alpha -difluoro- Delta4-pregnen-11 Beta -ol-3,20-dione.
 11. A composition as claimed in claim8 wherein the compound is 17 Alpha ,21-(1''-methoxy)-n-butylidenedioxy-6Alpha ,9 Alpha -difluoro- Delta 1,4-pregnadien-11 Beta -ol-3,20-dione.12. A method as claimed in claim 6 wherein from 0.0005% to 5% by weightof the compound is administered.
 13. A method as claimed in claim 6wherein from 0.005% to 0.5% by weight of the compound is administered.14. A method as claimed in claim 6 wherein the compound is 17 Alpha,21-(1''-methoxy)-n-butylidenedioxy-6 Alpha ,9 Alpha -difluoro- Delta4-pregnen-11 Beta -ol-3,20-dione.
 15. A method as claimed in claim 6wherein the compound is 17 Alpha ,21-(1''-methoxy)-n-butylidenedioxy-6Alpha ,9 Alpha -difluoro- Delta 1,4-pregnadien-11 Beta -ol-3,20-dione.